Long-term Metabolic Dysfunction Programming in Female Mice by Serial Moderate Restriction of a High-fat High-sucrose Diet.

BACKGROUND: While intermittent fasting leads to weight loss and improved glucose metabolism, food insecurity, the insufficient access to food for a healthy life, is associated with obesity and adverse cardiometabolic health, especially in women. We aimed to characterize the effects of intermittently restricted feeding on energy balance and glucose tolerance in female mice. METHODS: Female C57BL/6J mice were fed a high-fat, high-sucrose diet and intermittently food restricted to 60% of control littermates' ad libitum intake, starting at weaning and until week 19. Restricted mice were subsequently allowed ad libitum access to the same diet. Body composition and energy balance were measured at weeks 18.5, 19, 30, and 40. At week 42, mice underwent an intraperitoneal glucose tolerance test and plasma appetitive hormones measurements after nutrient gavage. RESULTS: During the food restriction phase, restricted mice accrued lower weight and fat mass than controls despite periodic ad libitum food access. Reintroduction of continuous ad libitum food caused increased food intake during the light phase and increased body mass in restricted mice. Minor differences in body composition-adjusted energy expenditure between groups were observed at week 40. At week 42, glucose tolerance was impaired in restricted mice compared to controls, and trends toward lower levels of postprandial anorexigenic hormones glucagon-like peptide-1 and pancreatic polypeptide were observed. CONCLUSION: Our findings suggest that repeated intermittent food restriction leads to changes in eating behavior that predispose to glucose intolerance when food is freely available. Future studies are needed to elucidate the specific mechanisms underlying these changes.

Prenatal High-Sucrose Diet Induced Vascular Dysfunction of Renal Interlobar Arteries in the Offspring via PPARγ-RXRg-ROS/Akt Signaling.

SCOPE: Prenatal nutrition imbalance correlates with developmental origin of cardiovascular diseases; however whether maternal high-sucrose diet (HS) during pregnancy causes vascular damage in renal interlobar arteries (RIA) from offspring still keeps unclear. METHODS AND RESULTS: Pregnant rats are fed with normal drinking water or 20% high-sucrose solution during the whole gestational period. Swollen mitochondria and distributed myofilaments are observed in vascular smooth muscle cells of RIA exposed to prenatal HS. Maternal HS increases phenylephrine (PE)-induced vasoconstriction in the RIA from adult offspring. NG-Nitro-l-arginine (L-Name) causes obvious vascular tension in response to PE in offspring from control group, not in HS. RNA-Seq of RIA is performed to reveal that the gene retinoid X receptor g (RXRg) is significantly decreased in the HS group, which could affect vascular function via interacting with PPARγ pathway. By preincubation of RIA with apocynin (NADPH inhibitor) or capivasertib (Akt inhibitor), the results indicate that ROS and Akt are the vital important factors to affect the vascular function of RIA exposure to prenatal HS. CONCLUSION: Maternal HS during the pregnancy increases PE-mediated vasoconstriction of RIA from adult offspring, which is mainly related to the enhanced Akt and ROS regulated by the weakened PPARγ-RXRg.

Sugar-Sweetened Beverages Consumption and Breast Cancer in Premenopausal and Postmenopausal Women.

BACKGROUND: The consumption of sugar-sweetened beverages (SSB), of which Mexico is a large consumer, has been associated with the risk of breast cancer. We assessed the association between SSBs consumption and breast cancer risk in pre- and postmenopausal women. METHODS: We performed a multicenter population-based case-control study in Mexico City, Monterrey, and Veracruz. We recruited 1,000 cases and 1,074 controls; all participants were pre- or postmenopausal women between 35 and 69 years of age. Diet before symptoms onset was assessed using a food frequency questionnaire. We conducted a multivariable-adjusted conditional logistic regression analysis stratified by menopausal status. RESULTS: For premenopausal women, after adjusting for matching characteristics, total energy intake and all potential confounders, the odds of having breast cancer in women who drank one or more SSBs servings per day showed 1.78 times the odds of those who drank one or fewer SSBs servings per month [OR = 1.78; 95% confidence interval (CI), 1.06-3.01]. For postmenopausal women, the corresponding model was not statistically significant (OR = 1.38, 95% CI, 0.84-2.25). We also observed higher consumption of SSBs among pre- than in postmenopausal women (23.3% and 17.4%, respectively among controls in the highest consumption category (≥1 per day). CONCLUSIONS: Our results suggest that SSBs consumption increases the risk of developing breast cancer, particularly in premenopausal women. IMPACT: Given the consumption of SSBs, of which Mexico is a large consumer, these results can support public policies to discourage the consumption of SSBs.

Total added sugar consumption is not significantly associated with risk for prediabetes among U.S. adults: National Health and Nutrition Examination Survey, 2013-2018.

Prediabetes affects 38% of U.S. adults and is primarily linked to added sugars consumed from sugar-sweetened beverages. It is unclear if total dietary intake of added sugar also increases the risk for prediabetes. This study examined if total (g/day) and percent intakes of <10%, 10-15%, or >15% added sugar increase the odds for prediabetes in U.S. adults. A cross-sectional, secondary analysis using 2013-2018 NHANES data was conducted. This study included data from U.S. adults ≥ 20 years with normoglycemia (N = 2,154) and prediabetes (N = 3,152) with 1-2 days of dietary recall information. Prediabetes was defined as a hemoglobin A1c of 5.7%-6.4% or a fasting plasma glucose of 100-125 mg/dL. Survey-weighted logistic regression was used to estimate odds ratios of prediabetes based on usual intakes of added sugar (total and percent intakes) using the National Cancer Institute Method. Differences in prediabetes risk and total and percent intakes of added sugar were compared by race/ethnicity. The sample's total energy intake from added sugar was 13.9%. Total (unadjusted: OR: 1.01, 95% CI: .99-1.00, p = .26; adjusted: OR: 1.00, 95% CI: .99-1.00, p = .91) and percent intakes of added sugar (unadjusted [<10%: (ref); 10-15%: OR: .93, 95% CI: .77-1.12, p = .44; >15%: OR: 1.03, 95% CI: .82-1.28, p = .82] and adjusted [<10%: (ref); 10-15%: OR: .82, 95% CI: .65-1.04, p = .09; >15%: OR: .96, 95% CI: .74-1.24, p = .73]) were not significantly associated with an increased odds of prediabetes. Prediabetes risk did not differ by race/ethnicity for total (unadjusted model [p = .65]; adjusted model [p = .51]) or percent (unadjusted model [p = .21]; adjusted model [p = .11]) added sugar intakes. In adults ≥20 years with normoglycemia and prediabetes, total added sugar consumption did not significantly increase one's risk for prediabetes and risk estimates did not differ by race/ethnicity. Experimental studies should expand upon this work to confirm these findings.

Meeting the Healthy People 2030 Added Sugars Target.

INTRODUCTION: Many Americans exceed the dietary recommendations for added sugars. Healthy People 2030 set a population target mean of 11.5% calories from added sugars for persons aged ≥2 years. This paper describes the reductions needed in population groups with varying added sugars intake to meet this target using four different public health approaches. METHODS: Data from the 2015-2018 National Health and Nutrition Examination Survey (n=15,038) and the National Cancer Institute method were used to estimate the usual percentage calories from added sugars. Four approaches investigated lowering intake among (1) the general U.S. population, (2) people exceeding the 2020-2025 Dietary Guidelines for Americans recommendation for added sugars (≥10% calories/day), (3) high consumers of added sugars (≥15% calories/day), or (4) people exceeding the Dietary Guidelines for Americans recommendation for added sugars with two different reductions on the basis of added sugars intake. Added sugars intake was examined before and after reduction by sociodemographic characteristics. RESULTS: To meet the Healthy People 2030 target using the 4 approaches, added sugars intake needs to decrease by an average of (1) 13.7 calories/day for the general population; (2) 22.0 calories/day for people exceeding the Dietary Guidelines for Americans recommendation; (3) 56.6 calories/day for high consumers; or (4) 13.9 and 32.3 calories/day for people consuming 10 to <15% and ≥15% calories from added sugars, respectively. Differences in added sugars intake were observed before and after reduction by race/ethnicity, age, and income. CONCLUSIONS: The Healthy People 2030 added sugars target is achievable with modest reductions in added sugars intake, ranging from 14 to 57 calories/day depending on the approach.

High Added Sugars Intake among US Adults: Characteristics, Eating Occasions, and Top Sources, 2015-2018.

The 2020−2025 Dietary Guidelines for Americans (DGA) recommends less than 10% of total daily calories come from added sugars. However, many adults overconsume added sugars putting them at risk for poor health outcomes. We examined characteristics of high added sugars consumers among US adults (≥20 years) and described their top 10 sources of added sugars intake using National Health and Nutrition Examination Survey 2015−2018 data (n = 9647). We defined high consumers as consuming >15% of daily calories from added sugars (1.5 times higher than the DGA). We used the National Cancer Institute method to estimate usual intake of energy and percent of calories from added sugars. Top 10 sources were identified based on their percentage contribution to total added sugars intake on a given day. T-tests were used to examine differences by age, sex, race/ethnicity, education, income, marital status, and weight status. Overall, mean usual total energy intake and added sugars intake was 2068 kcal/day and 264 kcal/day, respectively, and 30% of adults were classified as high consumers. The prevalence of high added sugars consumers was significantly higher among 20−30-year-olds (29%), 31−50-year-olds (33%), and 51−70-year-olds (29%) than those aged ≥70 years (22%); non-Hispanic Black (39%) and non-Hispanic White (31%) adults than Hispanics (26%); adults with

Consumption of Added Sugars by States and Factors Associated with Added Sugars Intake among US Adults in 50 States and the District of Columbia-2010 and 2015.

Purpose: The high intake of added sugars from foods or beverages increases the risk of obesity, hypertension, dyslipidemia, and cardiovascular disease. Because state-level data are lacking, we estimated dietary intake of added sugars by state and factors associated with intake among US adults. Design: Nationally representative, cross-sectional, in-person, household survey. Setting: 50 states and DC. Sample: 52,279 US adults from pooled data from 2010 and 2015 National Health Interview Surveys. Measures: Estimated total added sugars intake (tsp/day) using the National Cancer Institute's scoring algorithm that converts responses from the Dietary Survey Questionnaire screener to estimated total added sugars intake (tsp/day). Analysis: Mean dietary-added sugars intake estimates and standard error were calculated for adults' characteristics and by state for all 50 states and the District of Columbia. Differences by adult's characteristics were assessed by pairwise t-tests (p < 0.05). All analyses accounted for complex survey design and sampling weights. Results: Overall, US adults consumed 17.0 tsp of added sugars/day (range: 14.8 tsp/day in Alaska to 1.2 tsp/day in Kentucky). Added sugars intake varied by states and sociodemographic characteristics. Conclusion: Findings may inform efforts to reduce added sugars intake to lower the high burden of chronic disease.

The Effect of Alternating High-Sucrose and Sucrose Free-Diets, and Intermittent One-Day Fasting on the Estrous Cycle and Sex Hormones in Female Rats.

Relationships between diet, sex hormone concentrations, and the estrous cycle are important from the perspective of infertility and estrogen-dependent disease prevention and treatment. Four dietary interventions reflecting modern eating behaviors were explored. The study involved 50 female rats divided into five feeding groups. The impact of the amount of sucrose consumed (9% and 18% of the dietary energy content), alternating high-sucrose and sucrose-free diets, and a high-sucrose diet combined with intermittent one-day fasting on the estrous cycle and sex hormone concentrations in female rats was assessed. Even low amounts of dietary sucrose (9% of the dietary energy content) were found to lead to increased estradiol (E2) concentrations and decreased progesterone (Pg) concentrations. A high-sucrose diet, even when periodically applied, additionally led to a reduced concentration of luteinizing hormone (LH). The largest changes in the hormones tested were observed with one-day fasting coupled with the high-sucrose diet; in addition, the estrous phase was shortened and the estrous cycle was disrupted. The results of this study show that both the amount of dietary sucrose and also its uptake pattern affect the estrous cycle and sex hormone concentrations in female rats.

Kithul (Caryota urens) treacle: A healthy natural sweetener?

Introduction: Incidence of non communicable diseases such as diabetes, cardiovascular disease (CVD), several forms of cancer, hypertension, obesity etc is increasing in our country. It is suggested that these diseases can be moderated, in part, by consuming foods that produce a low blood sugar response. It is presumed that kithul treacle is comparable to simple sugars for sweetness, although currently the beneficial effects are not widely known. Objectives: To assess the chemical composition and glycaemic indices (GI) of kithul treacle and confectionary (aluwa) made using table sugar and kithul treacle. Methods: Chemical composition was analysed with standard AOAC methods. FAO/WHO guidelines were used to determine the glycaemic responses with glucose as the standard. Results: The moisture, crude protein, crude fat, total carbohydrate, starch & glucose and total dietary fibre contents of treacle were 28%, 0.3%, 7.9%, 81%, 28% and 2.20% (DM) with negligible ash content. Similarly both aluwa had negligible ash contents. Total carbohydrate (88-89%), fat (2.9%), protein (3.7-4.2%) and total dietary fibre (7.78-8.32%) contents of both aluwa were not significantly different. However, the digestible carbohydrate contents of treacle (67%) and sugar aluwa (59%) were significantly different (p<0.05). The GI of kithul treacle, aluwa made with treacle and sugar were 35, 55 and 63 respectively. Conclusion: Kithul treacle was categorized as a low GI food whereas both aluwa were categorized as medium GI foods. In comparison to aluwa made with table sugar, the glycaemic response of aluwa made with treacle was lower proving that replacing sugar with treacle leads to lower glycaemic response.

Association between added sugar intake and overall diet quality in the Finnish adult population.

Added sugar intake has been associated with several health issues, but few studies have examined its association with overall diet quality. We aimed at examining the association between added sugar intake and overall diet quality in Finnish adults. Associations between added sugar intake and sociodemographic factors, lifestyle factors, and BMI were also explored. Our data comprised 5094 adults residing in Finland who participated in the National FinHealth 2017 Study. Dietary intake was assessed by a validated FFQ. Food consumption and nutrient intakes were calculated using the Finnish national food composition database. Added sugar intake was estimated based on food categorisation and identifying naturally occurring sugar sources. Overall diet quality was assessed by the modified Baltic Sea Diet Score. The average added sugar intake was 7·6 E % in women and 8·3 E % in men in this study population. Added sugar intake was inversely associated with education (P = 0·03 women; P = 0·001 men), physical activity (P < 0·0001), and BMI in men (P = 0·003), and directly with smoking (P = 0·002 women; P < 0·0001 men). Added sugar intake was inversely associated with overall diet quality in both sexes (P < 0·0001). No interactions were found except for men's physical activity subgroups, the inverse association being stronger among active men than moderately active or inactive men (Pfor interaction = 0·005). Our findings suggest that high added sugar intake is associated with several unhealthy dietary and lifestyle habits, including poor-quality diets, smoking and leisure-time inactivity in Finnish adults. Efforts to improve diet quality should consider added sugar intake equally in the whole population.

High sucrose diet does not impact spatial cognition in rats using advanced touchscreen technology.

INTRODUCTION: Western diets, including those consisting of saturated fats, simple sugars and processed foods, is rising at an unprecedented rate. These lead to obesity and metabolic diseases, and possibly cognitive deficits. Exploring this, recent studies demonstrate marked impairment in spatial learning in rodents exposed to high-sugar diets. We utilised advanced touchscreen technology to assess several spatial and non-spatial components of cognition in rats chronically exposed to a high sucrose diet. METHODS: Male Wistar rats received 70 ml of 10% sucrose solution each day, or control tap water, persisting for the experiment duration (total n = 32). After 5 weeks of diet, rats performed Pairwise Discrimination, Location Discrimination, or Progressive Ratio tasks on automated touchscreens, and performance compared between groups. RESULTS: Sucrose rats consumed all the sugar solution provided to them, and had significantly increased caloric intake, compared to controls (p < 0.0001). However, in all tests, we found no significant difference in cognitive performance between Sucrose and Control treated rats. This included the number of trials for acquisition, and reversal, in Pairwise Discrimination, and number of trials required to complete Location Discrimination (p > 0.05 for all outcomes). No differences were observed in perseverative behaviour, motivation levels, or processing speed. CONCLUSION: Our study found no evidence to suggest that chronic consumption of sucrose impairs cognition, including both spatial and non-spatial learning tasks. These findings suggest that not all aspects of spatial cognition are negatively impacted by high sugar diet in rodents, and that particular use of touchscreen technology may probe different aspects of cognition than traditional tasks.

Does FGF21 Mediate the Potential Decrease in Sweet Food Intake and Preference Following Bariatric Surgery?

The liver-derived hormone fibroblast growth factor 21 (FGF21) has recently been linked to preference for sweet-tasting food. We hypothesized, that surgery-induced changes in FGF21 could mediate the reduction in sweet food intake and preference following bariatric surgery. Forty participants (35 females) with severe obesity (BMI ≥ 35 kg/m2) scheduled for roux-en-y gastric bypass (n = 30) or sleeve gastrectomy (n = 10) were included. Pre- and postprandial responses of intact plasma FGF21 as well as intake of sweet-tasting food assessed at a buffet meal test, the hedonic evaluation of sweet taste assessed using an apple juice with added sucrose and visual analog scales, and sweet taste sensitivity were assessed before and 6 months after bariatric surgery. In a cross-sectional analysis pre-surgery, pre- and postprandial intact FGF21 levels were negatively associated with the hedonic evaluation of a high-sucrose juice sample (p = 0.03 and p = 0.02). However, no changes in pre- (p = 0.24) or postprandial intact FGF21 levels were found 6 months after surgery (p = 0.11), and individual pre- to postoperative changes in pre- and postprandial intact FGF21 levels were not found to be associated with changes in intake of sweet foods, the hedonic evaluation of sweet taste or sweet taste sensitivity (all p ≥ 0.10). In conclusion, we were not able to show an effect of bariatric surgery on circulating FGF21, and individual postoperative changes in FGF21 were not found to mediate an effect of surgery on sweet food intake and preference.

High-Fat and Combined High-Fat and Sucrose Diets Promote Cardiac Oxidative Stress Independent of Nox2 Redox Regulation and Obesity in Rats.

BACKGROUND/AIMS: Oxidative stress is associated with cardiometabolic alterations, and the involvement of excess glucose and fatty acids has been demonstrated in this process. Thus, the aim of this study was to investigate the effects of different hypercaloric diets on cardiac oxidative stress. METHODS: Wistar rats were randomized into four groups: control (C), high-sucrose (HS), high-fat (HF), and high-fat with sucrose (HFS). Nutritional assessment, food profiles, histological analysis, comorbidities, and cardiovascular characteristics were determined. Cardiac oxidative stress was analyzed by malondialdehyde (MDA) and carbonylated proteins, and the cardiac protein expression levels of type 1 angiotensin receptor (AT-1), nicotinamide adenine dinucleotide phosphate oxidase 2 (Nox2), superoxide dismutase (SOD 1 e 2), glutathione peroxidase (GPX), and catalase (CAT) were determined by western blot. RESULTS: The HF group showed an increase in adiposity; however, it did not present adipocyte hypertrophy and comorbidities. Cardiac MDA and carbonylated protein levels were higher in the HF and HFS compared with the C group. The levels of oxidant and antioxidant proteins showed no difference between the groups. CONCLUSION: HF and HFS dietary interventions promoted cardiac oxidative stress, in the presence and absence of obesity, respectively. However, this process was neither mediated by the pro-oxidants AT1 and Nox2, nor by the quantitative reduction of antioxidant enzymes.

Distinct mechanisms involving diacylglycerol, ceramides, and inflammation underlie insulin resistance in oxidative and glycolytic muscles from high fat-fed rats.

This study investigated whether oxidative and glycolytic rat skeletal muscles respond differently to a high-fat (HF) sucrose-enriched diet with respect to diacylglycerol (DAG) and ceramides accumulation, protein kinase C (PKC) activation, glucose metabolism, and the expression of inflammatory genes. HF diet (8 weeks) suppressed insulin-stimulated glycogen synthesis and glucose oxidation in soleus (Sol), extensor digitorum longus (EDL) and epitrochlearis (Epit) muscles. However, DAG and ceramides levels increased in Sol and EDL, but not in Epit muscles of HF-fed rats. Additionally, membrane-bound PKC-delta and PKC-theta increased in Sol and EDL, whereas in Epit muscles both PKC isoforms were reduced by HF diet. In Epit muscles, HF diet also increased the expression of tumor necrosis factor-α (TNF-α) receptors (CD40 and FAS), toll-like receptor 4 (TLR4), and nuclear factor kappa light polypeptide gene enhancer in B cells (NF-kB), whereas in Sol and EDL muscles the expression of these inflammatory genes remained unchanged upon HF feeding. In conclusion, HF diet caused DAG and ceramides accumulation, PKC activation, and the induction of inflammatory pathways in a fiber type-specific manner. These findings help explain why oxidative and glycolytic muscles similarly develop insulin resistance, despite major differences in their metabolic characteristics and responsiveness to dietary lipid abundance.

Hypoglycemic effect of astragaloside IV via modulating gut microbiota and regulating AMPK/SIRT1 and PI3K/AKT pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Radix Astragali, the dried root of Astragalus mongholicus Bunge, has long been used in traditional Chinese Medicine to treat diabetes. Astragaloside IV (AS-IV), one of the most active ingredients in the root, has been shown to have anti-diabetes ability; however, its underlying mechanism is still unclear. MATERIALS AND METHODS: In this study, we evaluated the hypoglycemic effect and possible mechanisms of AS-IV in diabetic mice and insulin resistance-HepG2 cells. The components of the intestinal microflora in mice with type 2 diabetes mellitus (T2DM) were determined using high-throughput 16S rRNA gene sequencing. Moreover, the molecular mechanisms of specific members of insulin signaling pathways were analyzed. RESULTS: AS-IV significantly reversed the abnormalities in blood lipids, glucose, insulin resistance, as well as oxidative stress levels in T2DM mice. Histological finding showed that AS-IV could protect the cellular architecture of the liver and pancreas. AS-IV also regulated the abundance and diversity of intestinal flora of T2DM mice in a positive direction and increased butyric acid levels. The active role of AS-IV as an anti-diabetic compound by regulating the AMPK/SIRT1 and PI3K/AKT signaling pathways was revealed using a T2DM model and verified through the intervention of inhibitors using insulin-resistance HepG2 cells. CONCLUSION: Our results suggested that AS-IV may be used as an anti-diabetic drug candidate owing to its effects of regulating gut microbiota and AMPK/SIRT1 and PI3K/AKT signaling pathways.

Effect of δ-Tocopherol on Mice Adipose Tissues and Mice Adipocytes Induced Inflammation.

The study aim was to evaluate the potential anti-inflammatory effects of vitamin E analogs, especially α-tocopherol and δ-tocopherol. We used male C57BL/6JJcl mice, which were divided into four groups: the control (C), high-fat and high-sucrose diet (H), high-fat and high-sucrose diet+α-tocopherol (Ha) and high-fat and high-sucrose diet+δ-tocopherol (Hd) groups. The mice were fed for 16 weeks. To the high-fat and high-sucrose diet, 800 mg/kg of α-tocopherol or δ-tocopherol was added more. The final body weight was significantly higher in the H group than in the C group. On the other hand, the final body weight was drastically lower in the Ha group and Hd group than in the H group. However, the energy intake was not significantly different among all groups. Therefore, we assumed that α-tocopherol and δ-tocopherol have potential anti-obesity effect. Besides, inflammatory cytokine gene expression was significantly higher in the epididymal fat of the H group than in the C group. These results showed that inflammation was induced by epididymal fat of mice fed a high-fat and high-sucrose diet for 16 weeks. Unfortunately, addition of α-tocopherol or δ-tocopherol to the diet did not restrain inflammation of epididymal fat. Investigation of the anti-inflammatory effects of α-tocopherol or δ-tocopherol in co-cultured 3T3-L1 cells and RAW264.7 cells showed that δ-tocopherol inhibited increased gene expression of the inflammatory cytokines, IL-1ß, IL-6, and iNOS. These results suggest that an anti-inflammatory effect in the δ-tocopherol is stronger than that in the α-tocopherol in vitro. We intend to perform an experiment by in vivo sequentially in the future.

Palmitoyl-CoA effect on cytochrome c release, a key process of apoptosis, from liver mitochondria of rat with sucrose diet-induced obesity.

Cytochrome c (cyt-c) release from the mitochondria to the cytosol is a key process in the initiation of hepatocyte apoptosis involved in the progression of non-alcoholic fatty liver disease (NAFLD) to fibrosis, cirrhosis and hepatocellular carcinoma. Hepatocyte apoptosis may be related to lipotoxicity due to the accumulation of palmitic acid and palmitoyl-CoA (Pal-CoA). Therefore, the aim of this study is to examine whether Pal-CoA induces cyt-c release from liver mitochondria of sucrose-fed rat (SF). Pal-CoA-induced cyt-c release was sensitive to cyclosporine A indicating the involvement of the mitochondrial membrane permeability transition (mMPT). In addition, cyt-c release from SF mitochondria remains significantly lower than C mitochondria despite the increased rate of H2O2 generation in SF mitochondria. The decreased cyt-c release from SF may be also related to the increased proportion of the palmitic acid-enriched cardiolipin, due to the high availibilty of palmitic acid in SF liver. The enrichment of cardiolipin molecular species with palmitic acid makes cardiolipin more resistant to peroxidation, a mechanism involved in the dissociation of cyt-c from mitochondrial inner membrane. These results suggest that Pal-CoA may participate in the progression of NAFLD to more severe disease through mechanisms involving cyt-c release and mMPT, a key process of apoptosis.

Feeding diversified protein sources exacerbates hepatic insulin resistance via increased gut microbial branched-chain fatty acids and mTORC1 signaling in obese mice.

Animal models of human diseases are classically fed purified diets that contain casein as the unique protein source. We show that provision of a mixed protein source mirroring that found in the western diet exacerbates diet-induced obesity and insulin resistance by potentiating hepatic mTORC1/S6K1 signaling as compared to casein alone. These effects involve alterations in gut microbiota as shown by fecal microbiota transplantation studies. The detrimental impact of the mixed protein source is also linked with early changes in microbial production of branched-chain fatty acids (BCFA) and elevated plasma and hepatic acylcarnitines, indicative of aberrant mitochondrial fatty acid oxidation. We further show that the BCFA, isobutyric and isovaleric acid, increase glucose production and activate mTORC1/S6K1 in hepatocytes. Our findings demonstrate that alteration of dietary protein source exerts a rapid and robust impact on gut microbiota and BCFA with significant consequences for the development of obesity and insulin resistance.